Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Dan E Arking; Sara L Pulit; Lia Crotti; Pim van der Harst; Patricia B Munroe; Tamara T Koopmann; Nona Sotoodehnia; Elizabeth J Rossin; Michael Morley; Xinchen Wang; Andrew D Johnson; Alicia Lundby; Daníel F Gudbjartsson; Peter A Noseworthy; Mark Eijgelsheim; Yuki Bradford; Kirill V Tarasov; Marcus Dörr; Martina Müller-Nurasyid; Annukka M Lahtinen; Ilja M Nolte; Albert Vernon Smith; Joshua C Bis; Aaron Isaacs; Stephen J Newhouse; Daniel S Evans; Wendy S Post; Daryl Waggott; Leo-Pekka Lyytikäinen; Andrew A Hicks; Lewin Eisele; David Ellinghaus; Caroline Hayward; Pau Navarro; Sheila Ulivi; Toshiko Tanaka; David J Tester; Stéphanie Chatel; Stefan Gustafsson; Meena Kumari; Richard W Morris; Asa T Naluai; Sandosh Padmanabhan; Alexander Kluttig; Bernhard Strohmer; Andrie G Panayiotou; Maria Torres; Michael Knoflach; Jesper V Olsen; Kasper Lage Hansen; CARe Consortium

doi:10.1038/ng.3014

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Dan E Arking, Sara L Pulit, Lia Crotti, Pim van der Harst, Patricia B Munroe, Tamara T Koopmann, Nona Sotoodehnia, Elizabeth J Rossin, Michael Morley, Xinchen Wang, Andrew D Johnson, Alicia Lundby, Daníel F Gudbjartsson, Peter A Noseworthy, Mark Eijgelsheim, Yuki Bradford, Kirill V Tarasov, Marcus Dörr, Martina Müller-Nurasyid, Annukka M LahtinenIlja M Nolte, Albert Vernon Smith, Joshua C Bis, Aaron Isaacs, Stephen J Newhouse, Daniel S Evans, Wendy S Post, Daryl Waggott, Leo-Pekka Lyytikäinen, Andrew A Hicks, Lewin Eisele, David Ellinghaus, Caroline Hayward, Pau Navarro, Sheila Ulivi, Toshiko Tanaka, David J Tester, Stéphanie Chatel, Stefan Gustafsson, Meena Kumari, Richard W Morris, Asa T Naluai, Sandosh Padmanabhan, Alexander Kluttig, Bernhard Strohmer, Andrie G Panayiotou, Maria Torres, Michael Knoflach, Jesper V Olsen, Kasper Lage Hansen, CARe Consortium

158 Citationer (Scopus)

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	46
Udgave nummer	8
Sider (fra-til)	826-838
Antal sider	13
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3014
Status	Udgivet - aug. 2014

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10.1038/ng.3014

Citationsformater

Arking, D. E., Pulit, S. L., Crotti, L., van der Harst, P., Munroe, P. B., Koopmann, T. T., Sotoodehnia, N., Rossin, E. J., Morley, M., Wang, X., Johnson, A. D., Lundby, A., Gudbjartsson, D. F., Noseworthy, P. A., Eijgelsheim, M., Bradford, Y., Tarasov, K. V., Dörr, M., Müller-Nurasyid, M., ... CARe Consortium (2014). Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nature Genetics, 46(8), 826-838. https://doi.org/10.1038/ng.3014

Arking, DE, Pulit, SL, Crotti, L, van der Harst, P, Munroe, PB, Koopmann, TT, Sotoodehnia, N, Rossin, EJ, Morley, M, Wang, X, Johnson, AD, Lundby, A, Gudbjartsson, DF, Noseworthy, PA, Eijgelsheim, M, Bradford, Y, Tarasov, KV, Dörr, M, Müller-Nurasyid, M, Lahtinen, AM, Nolte, IM, Smith, AV, Bis, JC, Isaacs, A, Newhouse, SJ, Evans, DS, Post, WS, Waggott, D, Lyytikäinen, L-P, Hicks, AA, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, DJ, Chatel, S, Gustafsson, S, Kumari, M, Morris, RW, Naluai, AT, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, AG, Torres, M, Knoflach, M, Olsen, JV, Hansen, KL & CARe Consortium 2014, 'Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization', Nature Genetics, bind 46, nr. 8, s. 826-838. https://doi.org/10.1038/ng.3014

@article{de88922436084bcab7ebc4a5399153ed,

title = "Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization",

abstract = "The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.",

author = "Arking, {Dan E} and Pulit, {Sara L} and Lia Crotti and {van der Harst}, Pim and Munroe, {Patricia B} and Koopmann, {Tamara T} and Nona Sotoodehnia and Rossin, {Elizabeth J} and Michael Morley and Xinchen Wang and Johnson, {Andrew D} and Alicia Lundby and Gudbjartsson, {Dan{\'i}el F} and Noseworthy, {Peter A} and Mark Eijgelsheim and Yuki Bradford and Tarasov, {Kirill V} and Marcus D{\"o}rr and Martina M{\"u}ller-Nurasyid and Lahtinen, {Annukka M} and Nolte, {Ilja M} and Smith, {Albert Vernon} and Bis, {Joshua C} and Aaron Isaacs and Newhouse, {Stephen J} and Evans, {Daniel S} and Post, {Wendy S} and Daryl Waggott and Leo-Pekka Lyytik{\"a}inen and Hicks, {Andrew A} and Lewin Eisele and David Ellinghaus and Caroline Hayward and Pau Navarro and Sheila Ulivi and Toshiko Tanaka and Tester, {David J} and St{\'e}phanie Chatel and Stefan Gustafsson and Meena Kumari and Morris, {Richard W} and Naluai, {Asa T} and Sandosh Padmanabhan and Alexander Kluttig and Bernhard Strohmer and Panayiotou, {Andrie G} and Maria Torres and Michael Knoflach and Olsen, {Jesper V} and Hansen, {Kasper Lage} and {CARe Consortium}",

year = "2014",

month = aug,

doi = "10.1038/ng.3014",

language = "English",

volume = "46",

pages = "826--838",

journal = "Nature: New biology",

issn = "1061-4036",

publisher = "nature publishing group",

number = "8",

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TY - JOUR

T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

AU - Arking, Dan E

AU - Pulit, Sara L

AU - Crotti, Lia

AU - van der Harst, Pim

AU - Munroe, Patricia B

AU - Koopmann, Tamara T

AU - Sotoodehnia, Nona

AU - Rossin, Elizabeth J

AU - Morley, Michael

AU - Wang, Xinchen

AU - Johnson, Andrew D

AU - Lundby, Alicia

AU - Gudbjartsson, Daníel F

AU - Noseworthy, Peter A

AU - Eijgelsheim, Mark

AU - Bradford, Yuki

AU - Tarasov, Kirill V

AU - Dörr, Marcus

AU - Müller-Nurasyid, Martina

AU - Lahtinen, Annukka M

AU - Nolte, Ilja M

AU - Smith, Albert Vernon

AU - Bis, Joshua C

AU - Isaacs, Aaron

AU - Newhouse, Stephen J

AU - Evans, Daniel S

AU - Post, Wendy S

AU - Waggott, Daryl

AU - Lyytikäinen, Leo-Pekka

AU - Hicks, Andrew A

AU - Eisele, Lewin

AU - Ellinghaus, David

AU - Hayward, Caroline

AU - Navarro, Pau

AU - Ulivi, Sheila

AU - Tanaka, Toshiko

AU - Tester, David J

AU - Chatel, Stéphanie

AU - Gustafsson, Stefan

AU - Kumari, Meena

AU - Morris, Richard W

AU - Naluai, Asa T

AU - Padmanabhan, Sandosh

AU - Kluttig, Alexander

AU - Strohmer, Bernhard

AU - Panayiotou, Andrie G

AU - Torres, Maria

AU - Knoflach, Michael

AU - Olsen, Jesper V

AU - Hansen, Kasper Lage

AU - CARe Consortium

PY - 2014/8

Y1 - 2014/8

N2 - The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

AB - The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

U2 - 10.1038/ng.3014

DO - 10.1038/ng.3014

M3 - Journal article

C2 - 24952745

SN - 1061-4036

VL - 46

SP - 826

EP - 838

JO - Nature: New biology

JF - Nature: New biology

IS - 8

ER -

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization

Abstract

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